Lupus Research Gets Personal

Scientists unleash wave of new findings

A fresh wave of research is bringing personalized medicine closer to reality for children living with an often-misunderstood autoimmune disease − systemic lupus erythematosus.

While primarily an adult disease, 15 to 20 percent of lupus cases emerge during childhood.

These children face higher risks than adults of kidney damage, brain inflammation and future infertility. Meanwhile, facial rashes, painful skin lesions, sensitivity to sunlight and a high risk of developing arthritis combine to make it difficult for children with lupus to stay active.

However, scientists at Cincinnati Children’s say advances on several research fronts – from an explosion in basic genetic research to developing medications specifically approved for use in children with lupus – will soon make it possible for specialists to offer better care and more hope to families.

‘Tsunami of data’

John Harley, MD, PhD, says a “tsunami of data” at the molecular level is transforming our basic understanding of lupus.

Harley joined Cincinnati Children’s last year to direct the medical center’s Division of Rheumatology, which has a long history as a leader in drug research for juvenile idiopathic arthritis (JIA) and other autoimmune diseases.

For nearly two decades, Harley played key roles in the world’s largest effort to gather genetic data about lupus as a researcher at the Oklahoma Medical Research Foundation. In 1994, Harley created the Lupus Multiplex Registry and Repository, an important collection of biological samples. In 1997, Harley and colleague Judith James, MD, PhD, established a link between lupus and Epstein-Barr virus (EPV). In 2003, they also reported that antibodies appear in the blood years before lupus patients show any outward symptoms.

At Cincinnati Children’s, Harley oversees the new Center for Autoimmune Genomics and Etiology (CAGE) to continue studying the genetic roots of lupus and related conditions. So far, investigators have reported about 35 genes associated with lupus, a vast increase from about seven that were known in 2007. These findings demonstrate both the complexity of the disease and the hope that new technology can bring to bear.

Harley spoke about this explosion of genetic data in Vancouver in June 2010 at the Lupus Foundation of America’s Ninth International Congress on Lupus.

“Every one of these genes has its own story to tell. Their effects, relatively speaking, are small. But they are real,” Harley told the foundation. “And they represent an enormous new potential for understanding where lupus comes from.”

Less than a decade ago, the ability to analyze 300 genotypes a day was considered impressive, Harley says. But now, newer systems can process 100 million genotypes in a day.
“Personalized medicine is under way,” Harley says. “We are making exciting progress against an almost impossible, intractable problem.”

The process of identifying and mapping the genes in lupus can open many doors, he says: new targets for drug therapy, more precise diagnostic tests, better outcomes.

New Challenges 

Until the last few years, the challenge in genetic research had been the massive effort it took simply to find gene associations. Now the challenge is keeping up with vastly increased technical capacity.

“Now that we’ve discovered so many genes, it becomes impossible to remember all the relationships and interactions. It’s changing how we do research. It’s changing how we think,” Harley says.

The new Center for Autoimmune Genomics was formed to study the complex interactions of genetics, the immune system and environmental factors such as infection, stress, exercise and diet. The center’s goals include building even larger bio-repositories of gene samples from cases, controls and family members.

The task will involve Cincinnati Children’s working with research centers worldwide to assemble more data. Researchers here also expect to glean important research information from the medical center’s new electronic medical records system, launched in 2010.

“There’s a bottleneck in research; nobody wants to pay for assembling subjects. But Cincinnati Children’s has a powerful asset,” Harley says. “We have more than 1 million patient contacts a year, and more than 70,000 new patients being added to the system each year.”

Protecting children as they grow

While basic genetic research continues, clinical research at Cincinnati Children’s focuses on finding ways to protect against damage to the kidneys, brain and ovaries that can occur with lupus.

Lupus, first described in the 13th century, remains difficult to diagnose and treat. But much progress has been made. As recently as 50 years ago, half the people with lupus died within four years. Today, however, five-year survival is 97 percent, according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“For reasons that are not quite understood, the disease is much more active and severe in children,” says Hermine Brunner, MD, MSc, a pediatric rheumatologist who heads the Lupus Center at Cincinnati Children’s. “About 20 percent of adults with lupus have kidney disease, whereas 60 to 80 percent of children will have kidney disease. And the disease stays active over time more often in children.”

Brunner and colleagues at Cincinnati Children’s are pursuing several lines of research, including improved tests to track kidney and brain damage, methods for more accurate dosing and more refined standards of care for lupus.

“Believe it or not, there’s not a single medication that’s FDA approved for children with lupus. Whatever we use now is off-label,” Brunner says. “But that is starting to change.”